Heparin is a naturally occurring GAG (glucosaminoglycan) that is synthesized by and stored intracellulary in so-called mast cells in humans and animals. Prepared industrially from porcine intestinal mucosa, heparin is a potent anticoagulant and has been used clinically for more than 60 years as the drug of preference for prophylaxis and treatment of thromboembolic disorders. The major potential adverse effects of heparin treatment are bleeding complications caused by its anticoagulant properties. Heparin is highly polydisperse and composed of a heterogeneous population of polysaccharides with molecular weights ranging from 5 to 40 kDa, with the average being approximately 15 to 18 kDa. Low molecular weight/mass heparins (LMWH) according to European pharmacopeia 6.0 are defined as “salts of sulfated GAGs having a mass-average molecular mass less than 8 and for which at least 60 per cent of the total mass has a molecular mass less than 8 kDa.” Low molecular mass heparins display different chemical structures at the reducing or the non-reducing end of the polysaccharide chains.” “The potency is not less than 70 IU of anti-factor Xa activity per milligram calculated with reference to the dried substance. The ratio of anti-factor Xa activity to anti-factor Ha activity is not less than 1.5.” Clinically used LMWHs have molecular weights ranging from 3 to 15 kDa with an average of approximately 4 to 7 kDa. Produced by controlled depolymerization/fractionation of heparin, LMWHs exhibits more favorable pharmacological and pharmacokinetic properties, including a lower tendency to induce hemorrhage, increased bioavailability and a prolonged half-life following subcutaneous injection.
Heparin exerts its anticoagulant activity primarily through high-affinity binding to and activation of the serine proteinase inhibitor, antithrombin (AT). Binding is mediated by a specific pentasaccharide sequence. AT, an important physiological inhibitor of blood coagulation, neutralizes activated coagulation factors by forming a stable complex with these factors. Binding of heparin causes a conformational change in AT that dramatically enhances the rate of inhibition of coagulation factors, thereby attenuating blood coagulation and the formation of blood clots.
Infection caused by Plasmodium falciparum frequently gives rise to severe malaria in humans. Parasitized erythrocytes (pE) have the ability to bind (in vivo: sequestrate) in the deep microvasculature as well as to uninfected erythrocytes, so called rosetting. The sequestration and rosetting of pE augments the generation of severe disease when binding is excessive; blocking the blood-flow, reducing oxygen delivery and causing tissue damage. Heparin has been suggested as a useful agent in the treatment of the pathology occurring during severe malaria. Heparin was previously used in the treatment of severe malaria because of the suggested presence of disseminated intravascular coagulation (DIC) in malaria patients but it was discontinued due to the occurrence of severe side effects such as intracranial bleedings. Moreover, it was found that pE aggregation is not primarily due to blood coagulation, but to noncovalent interactions between a parasite-induced protein on pE surfaces and heparan sulfate (a heparin-related GAG) on erythrocytes and vascular endothelial cells. The effect of heparin is ascribed to its ability to compete out this interaction (Vogt et al., PloS Pathog. 2006; 2, e100). Hence, there is a medical need for a heparin derivative with a markedly reduced anticoagulant activity and bleeding inducing potential designed with respect to its distribution of suitable sized and charged chains. U.S. Pat. No. 5,472,953 (Ekre et al) discloses the use of heparins with reduced anticoagulant activity for the treatment of malaria.
A M Leitgeib et al. in Am. J. Trop. Med. Hyg. 2011, vol. 84(3), pp. 380-396 report promising studies with low anticoagulant heparins which are found to disrupt rosettes of fresh clinical isolates from patients with malaria.
In summary, a heparin derivative that carries the polyanionic features of heparin in essential respects, but lacks an anticoagulant effect would be an excellent candidate for treating maladies in which the anticoagulant effect of heparin would be considered as a serious side effect.